Marijuana doesn’t count, does it?” Clinicians are familiar with this common reply when screening for drug use. Cannabis—the most common illicit substance—has managed to exempt itself from the hazardous reputation held by other illicit drugs.¹

As mental health practitioners, it is our duty to educate our patients about the potential harms and consequences of cannabis use. This important task is complicated by the disagreement and uncertainty surrounding the nature of the interaction between cannabis and psychotic disorders.

While research suggests that cannabis use can induce an acute psychotic state, there is controversy about whether it may precipitate psychotic disorders, such as schizophrenia. In this article, we provide an update on the literature on this important issue, emphasize areas in need of research, and provide clinically useful recommendations.

More than 16 million Americans use cannabis on a regular basis, typically beginning in adolescence. Notably, it is estimated that approximately 4% of the population has a diagnosis of either cannabis abuse or dependence.¹ A history of cannabis misuse is even more common in patients who are schizophrenic than in the general population; 25% of patients with schizophrenia have a comorbid cannabis use disorder. Cannabis use disorders are especially common in younger and first-episode patient samples and in samples with high proportions of males.²

Neurobiology

Marijuana contains more than 400 chemical compounds, including over 60 cannabinoids that contribute to its psychopharmacological effects. The primary psychoactive constituent of cannabis is delta-9-tetrahydrocannabinol (THC). Other plant cannabinoids include delta-8-tetrahydrocannabinol; cannabinol; and cannabidiol (CBD); CBD is the second major psychoactive constituent of cannabis.³ The ratios of these and other cannabinoids vary enormously in preparations of cannabis, and little information exists about the concentration of each of the particular cannabinoids in commonly used cannabis products. Concerns have been expressed regarding the large increase in the potency of cannabis and the surrounding health implications. In the 1960s, the THC content was thought to be in the range of 1% to 3%; today it can reach up to 20%.⁴

The endogenous cannabinoid system consists of 2 types of G-protein-coupled receptors: cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. CB1 receptors are the most abundant in the brain, while CB2 receptors predominate on immune cells. CB1 receptors are highly concentrated in brain regions implicated in the putative neural circuitry of psychosis and cognitive function. These include the hippocampus, prefrontal cortex, anterior cingulate, basal ganglia, cerebellum, and cortex, with lower levels present in the thalamus, hypothalamus, and amygdala. Activation of CB1 receptors mediates the behavioral and physiological effects of both endogenous and exogenous cannabinoids in the brain.⁴

An important role of the CB1 receptor is to modulate neurotransmitter release in a manner that maintains homeostasis by preventing excessive neuronal activity in the CNS.⁵ CB1 receptors are localized on presynaptic neuron terminals on both inhibitory and excitatory neurons, yet they predominate on γ-aminobutyric acid interneurons.⁶ It is the inhibitory neurons that are thought to mediate most of the effects of cannabinoids. In addition, the action of cannabinoids includes interactions, albeit indirectly, with the dopaminergic system.

THC is a partial agonist at the CB1 receptors, where it has modest affinity and low intrinsic activity. In contrast, CBD shows very little affinity for CB1 receptors. Moreover, the precise molecular mechanism of action of CBD remains unclear. The main endocannabinoids are anandamide and 2-arachidonylglycerol. In contrast to classic neurotransmitters, endocannabinoids can function as retrograde synaptic messengers—they are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release.

Cannabinoids produce an increase in the dopaminergic activity in the mesolimbic reward pathway, which plays a pivotal role in mediating the reinforcing effects of most drugs of abuse. The increased dopaminergic drive elicited by the cannabinoids could underlie the abusive property of the drug and increases in positive psychotic symptoms induced by THC.⁷ Recurrent cannabis use produces prolonged and excessive stimulation of the CB1 receptor, and this is thought to disrupt endocannabinoid system function.⁸ Several lines of evidence exist to suggest a role for cannabinoids and their receptors in the pathophysiology of schizophrenia. It has also been proposed that this CB1 receptor overstimulation may be a contributing factor in triggering THC-induced psychosis.⁹